Anti-inflammatory imidazole compounds

ABSTRACT

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R 1  is selected from the group consisting of ##STR2## and --C.tbd.C--R&#39; and the remaining substituents are as defined hereinbelow and its non-toxic, pharmaceutically acceptable acid additon salts having anti-inflammatory activity and their preparation.

PRIOR APPLICATION

This application is a division of copending U.S. patent application Ser. No. 080,407 filed July 31, 1987, now U.S. Pat. No. 4,810,828.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel compounds of formula I and their non-toxic, pharmaceutically acceptable acid addition salts and their preparation.

It is another object of the invention to provide novel anti-inflammatory compositions and a novel method of treating inflammation in warm-blooded animals.

These and other objects and advantages of the invention will become obvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are selected from the group consisting of a compound of the formula ##STR3## wherein R₁ is selected from the group consisting of ##STR4## and --C.tbd.C--R', R is selected from the group consisting of hydrogen and alkyl of 1 to 5 carbon atoms, R' is selected from the group consisting of hydrogen, alkyl and hydroxyalkyl of 1 to 5 carbon atoms, and aryl of 6 to 10 carbon atoms optionally substituted with at least one member of the group consisting of halogen, --OH, --COOH, CF₃ and alkyl and alkoxy of 1 to 5 carbon atoms, (a) A is alkyl of 1 to 5 carbon atoms, B and G together with the carbon atom to which they are attached are carbonyl or thiocarbonyl and D is selected from the group consisting of alkyl of 1 to 5 carbon atoms and phenyl optionally substituted with at least one member of the group consisting of halogen, --OH, --COOH, --CF₃ and alkyl and alkoxy of 1 to 5 carbon atoms or (b) A and B together form a bond, G is selected from the group consisting of alkyl, alkoxy and alkylthio of 1 to 5 carbon atoms and alkylsulfinyl and alkylsulfonyl of 1 to 5 carbon atoms and D is selected from the group consisting of alkyl of 1 to 5 carbon atoms and phenyl optionally substituted with at least one member of the group consisting of halogen, --OH, --COOH, --CF₃ and alkyl and alkoxy of 1 to 5 carbon atoms or (c) A and B together form a bond, G and D together form a member of the group consisting of ##STR5## wherein X is alkoxy or alkylthio of 1 to 5 carbon atoms, Y and Y' are individually hydrogen or alkyl of 1 to 5 carbon atoms and E is hydrogen or halogen with the proviso when A and B are a bond and G and D together are ##STR6## E is other than hydrogen and its non-toxic, pharmaceutically acceptable acid addition salts,

When A and B together form a bond and G and D together form ##STR7## the compounds of formula I may have the formula ##STR8## respectively.

Examples of alkyl and alkoxy of 1 to 5 carbon atoms are methyl, ethyl, isopropyl, n-propyl and linear and branched butyl and pentyl, methoxy, ethoxy, isopropoxy, n-propoxy and linear and branched butoxy and pentyloxy. Examples of hydroxyalkyl of 1 to 5 carbon atoms are hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisopropyl and linear or branched hydroxybutyl and hydroxypentyl.

Examples of aryl of 6 to 10 carbon atoms are phenyl and naphthyl optionally substituted as discussed above. Examples of alkylthio of 1 to 5 alkyl carbon atoms are methylthio, ethylthio, n-propylthio, isopropylthio and linear and branched butylthio and pentylthio. Examples of alkylsulfinyl and alkylsulfonyl of 1 to 5 alkyl carbon atoms are methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, linear and branched butylsulfinyl and pentylsulfinyl, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-propylsulfonyl and linear and branched butylsulfonyl and pentylsulfonyl.

Examples of suitable acids for the formation of the non-toxic, pharmaceutically acceptable acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid and phosphoric acid and organic acids such as propionic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylyic acid, aspartic acid, alkanesulfonic acids such as methanesulfonic acid, and arylsulfonic acid such as benzenesulfonic acid.

Examples of preferred compounds of formula I are those wherein R₁ is ##STR9## and E is halogen, those wherein R₁ is --C.tbd.C--R' and E is halogen, those wherein A and B together are a bond, G and D together are ##STR10## E is halogen, X_(a) is methoxy or methylthio and Y_(a) and Y'_(a) are individually hydrogen, methyl or ethyl and E is halogen and those wherein A and B together are a bond, G is alkylthio of 1 to 5 carbon atoms and D is optionally substituted phenyl and their non-toxic, pharmaceutically acceptable acid addition salts.

Among the preferred compounds of formula I are

1-(3-bromo-6-ethyl-5-methyl-7-methylthioimidazo[1,2-a]-pyrimidin-2-yl)-2-methyl-2-propen-1-one;

1-[5-bromo-1-(4-ethylphenyl)-2-methylthioimidazol-4-yl]-2-methyl-2-propen-1-one;

1-[5-bromo-1-(4-methoxyphenyl)-2-methylthioimidazol-4-yl]-2-propen-1-one;

1-(3-bromo-6-ethyl-7-methoxy-5-methylimidazo[1,2-a]-pyrimidin-2-yl)-2-propen-1-one;

1-(3-bromo-6-ethyl-7-methoxy-5-methylimidazol[1,2-a]-pyrimidin-2-yl)-3-phenyl-2-propyn-1-one and their non-toxic, pharmaceutically acceptable acid addition salts.

The novel process of the invention for the preparation of compounds of formula I wherein E is hydrogen comprises oxidizing a compound of the formula ##STR11## wherein B,G,D,A and R₁ are defined as above with an oxidizing agent such as manganese dioxide and optionally salifying the corresponding compound of formula I. The oxidation is preferably effected in an organic solvent such as chloroform at reflux.

The compounds of formula IV may be prepared by reacting a compound of the formula ##STR12## wherein A,B,G and D have the above definitions with a source of R₁ ⁻ carbonions such as Grignard reagent of the formula R₁ MgBr III or an alkyllithium of the formula R₁ -Li III_(A) wherein R₁ has the above definition preferably in an inert organic solvent such as tetrahydrofuran.

A process for the preparation of compounds of formula I_(B) wherein E is halogen ##STR13## wherein Hal represents a halogen atom, R'₁ is ##STR14## or --C.tbd.C--R' wherein R and R' have the above definitions and (a) A' is alkyl of 1 to 5 carbon atoms, B' and G' together with the carbon atom to which they are attached are carbonyl or thiocarbonyl and D' is alkyl of 1 to 5 carbon atoms or phenyl optionally substituted with at least one member of the group consisting of halogen, --OH, --COOH, --CF₃ and alkyl and alkoxy of 1 to 5 carbon atoms or (b) A' and B' together form a bond, G' is alkyl or alkylthio of 1 to 5 carbon atoms and D' is alkyl of 1 to 5 carbon atoms or phenyl optionally substituted with at least one member of the group consisting of halogen, --OH, --COOH, CF₃ and alkyl and alkoxy of 1 to 5 carbon atoms or (c) A' and B' are a bond, G' and D' together are ##STR15## wherein X, Y and Y' are as defined above comprises reacting a compound of the formula ##STR16## wherein A', B', G', D' and R'₁ are defined as above with a N-halosuccinimide optionally followed by salification of the compound of formula I_(B). The reaction is preferably effected in an organic solvent such as chloroform or carbon tetrachloride.

A process for the preparation of a compound of the formula ##STR17## wherein R₁, D and E are defined as above, Alk is alkyl of 1 to 5 carbon atoms and n is 1 or 2 comprises oxidizing a compound of the formula ##STR18## wherein D,E,R₁ and Alk have the above definition and n' is 0 or 1 with an oxidizing agent such as sodium metaperiodate to obtain the compound of formula I_(D) which may be optionally salified. The reaction is preferably effected in a suitable organic solvent such as aqueous alkanol such as methanol and at a suitable temperature such as about 50° C.

To prepare the alkylsulfinyl derivatives, the compounds of formula I_(C) wherein n' is 0 are reacted with one equivalent of oxidizing agent. The alkylsulfonyl compounds of formula I_(D) wherein n is 2 may be prepared by oxidizing the compound of formula I_(C) wherein n' is 0 with at least two equivalents of oxidizing agent or oxidize the compound of formula I_(C) wherein n' is 1 with at least one equivalent of oxidizing agent.

A process for the preparation of the compounds of formula I wherein at least one of R₁ and D contains a hydroxy group comprises removing a protective group from a compound of the formula ##STR19## wherein A, B, G and E have the above definitions, D" is D or a precursor of a group D with a protected hydroxy and R"₁ is R₁ or a precursor of a group R₁ with a protected hydroxy, with the proviso that at least one of D" and R"₁ is a precursor of a group containing a protected hydroxy. The compounds of formula V may be prepared by one of the previous processes using starting materials wherein R₁ and/or D contains protected hydroxy groups.

As will be appreciated from the above, certain of the compounds of the invention possess free hydroxy groups, and it may thus be necessary or desirable to protect any free hydroxy groups during the preparation of the said compounds. In such situations, the protecting group will remain in place throughout the duration of the process sequence, and will itself be removed by traditional methods (e.g. by hydrolysis) as the final step thereof.

For example, if R' is hydroxyalkyl of 1 to 5 carbon atoms, the protecting group used will conveniently be of the type customarily employed for the protection of aliphatic hydroxy groups such as tetrahydropyranyl, although other suitable protecting groups will be apparent to those skilled in the art. Thus, a compound of formula III or III_(A) wherein R' of R₁ is a suitably protected hydroxyalkyl of 1 to 5 carbon atoms will be taken and reacted with the appropriate compound of formula II. The protected derivative of formula IV thereby obtained may then be elaborated as appropriate according to one or more of processes (A) to (C) above, the protecting group on the hydroxy substituent being retained for the remaining steps of the synthetic sequence, its removal consituting the final step thereof. Such a process is described in Examples 22 and 23.

Similarly, in those cases wherein R' is hydroxy-substituted aryl of 6 to 10 carbon atoms and/or D is a hydroxy-substituted phenyl, the protecting group used will conveniently be of the type customarily employed for the protection of aromatic hydroxys, a typical example being benzyl although as before other suitable protecting groups will be apparent to those skilled in the art. Again, the protected derivative of formula IV involved as an intermediate in the synthetic sequence may be elaborated as appropriate according to one or more of processes (A) to (C) above. As before, the protecting group on the hydroxy will be retained for the remaining steps of the synthetic sequence and its removal will constitute the final step thereof and such a process is described in Example 14.

The compounds are basic in character and their acid addition salts may be obtained by reacting approximately stoichiometric amounts of the compound of formula I and the appropriate acid in a suitable solvent with or without isolation of the compound of formula I

The novel anti-inflammatory compositions of the invention are comprised of an anti-inflammatorily effective amount of at least one compound of formula I and their non-toxic, pharmaceutically acceptable acid addition salts and an inert pharmaceutical carrier or excipient. The compositions may be in the form of tablets, dragees, capsules, powders, suppositories, aerosols and injectable solutions or suspensions.

Examples of suitable excipients are talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, animal or vegetable fats, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.

The compositions of the invention possess very interesting pharmacological properties; particularly they have been found to possess an anti-inflammatory effect, notably in their ability to moderate inflammatory/immune cell function by restricting arachidonic acid release and consequential eicosanoid biosynthesis. They are useful for the treatment of inflammatory and immunological disorders such as rheumatoid arthritis, osteoarthritis and psoriasis. The preferred active ingredients are as indicated above.

The novel method of the invention for treating inflammation in warm-blooded animals, including humans, comprises ad ministering to warm-blooded animals an anti-inflammatorily effective amount of at least one compound of formula I and their non-toxic, pharmaceutically acceptable acid addition salts. The compounds may be administered orally, rectally or parenterally and the usual daily dose is 0.001 to 2.5 mg/kg depending on the conditions treated, the specific compound and the method of administration.

Imidazole-4-carboxaldehydes of formula II may be prepared by a modification of the procedures described in Helv. Chim. Acta. 1960, Vol. 43, p. 1787 and Tetrahedron, 1963, Vol. 19, p. 1883. An example of such a preparation is given below as Preparation A.

Imidazo[1,2-a]pyrimidine-2-carboxaldehydes of formula II may be prepared as in British patent application No. 2,128,989 or by methods analogous thereto, as also may compounds of formula I_(A) wherein A' and B' together are a bond, G' and D' together are ##STR20## wherein X, Y and Y' are as defined above and R'₁ ##STR21## in which R is as defined above which, while not themselves being compounds of the invention, are nevertheless useful intermediates for the compounds of formula I_(B). An example of such a preparation is described in Preparation H below.

Imidazol[1,2-a]pyridine-2-carboxaldehydes of formula II may conveniently be prepared using a variant of the process described in British patent application No. 2,128,989 from the corresponding imidazo[1,2-a]pyridine-2-carboxylate esters which, in turn, may themselves be obtained by the method detailed in J. Org. Chem., 1965, Vol. 30, p. 2403.

In the following examples there are described several preferred embodiments to illustrate the invention. However, it is to be understood that the invention is not intended to be limited to the specific embodiments.

Preparation A: 1-(4-methoxyphenyl)-2-methylthioimidazole-4-carboxaldehyde ##STR22## STEP (a):

A mixture of 18 g of glucose, 12.3 of p-methoxyaniline, 36 ml of water and 1 ml of acetic acid was heated on a steam-bath for 15 minutes after which time a clear solution was formed. 7.6 g of ammonium isothiocyanate and 6 g of acetic acid were added and the solution was heated on a steam-bath for 2 hours after which time solidification occurred. The solid was digested with hot water, filtered, stirred in methanol for 1 hour, filtered, washed with ether and dried to obtain 10.5 g (32%) of intermediate (1) melting at 215°-6° C. (Tetrahedron, 1963, Vol. 19, page 1883, m.p. 215°-6° C.)

STEP (b):

A mixture of 10.5 g of intermediate (1) 5.0 g of iodomethane and 5.0 g of potassium carbonate was stirred in 50 ml of dimethylformamide for 1 hour and then was diluted with water to crystallize 7.6 g (69%) of intermediate (2) as a brown solid which was used directly in the next step.

STEP (c):

A mixture of 7.6 g of intermediate (2) and 16.0 g of sodium metaperiodate was stirred in 100 ml of aqueous methanol of 10% for 1 hour. The solution was concentrated under reduced pressure and diluted with water to crystallize 2.7 g of aldehyde (3) (49% yield) as colorless crystals after crystallization from ethanol melting at 118°-20° C.

Compounds B to E were prepared analogously. Compound F was prepared as described in published British patent application No. 2,128,989, and compound G was prepared by an analogous method. Compounds J and K were prepared as indicated in Example 1 Step A. The Yield, melting point and analytical data of starting compounds of formula II are given in Tables A and B. Yield, melting point and analytical data of intermediates of formula I_(A) are given in Table C.

EXAMPLE 1 1-(3-bromo-6-ethyl-5-methyl-7-methylthio-imidazo[1,2-a]pyrimidin-2-yl)-2-methyl-2-propen-1-one STEP A: 1-(6-ethyl-5-methyl-7-methylthioimidazo[1,2-a]pyrimidin-2-yl)-2-methyl-2-propen-1-one (Method A)

1.2 g (4.78 mmol) of 6-ethyl-5-methyl-7-methylthioimidazo[1,2-a]pyrimidine-2-carboxaldehyde were added to a solution of 7.17 mmol of 2-propenyl magnesium bromide in 50 ml of dry tetrahydrofuran under nitrogen and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with aqueous ammonium chloride and was extracted with chloroform (3×50 ml). The organic layer was dried over MgSO₄ and the solvent was removed under reduced pressure. The residual oil was purified by flash chromatography over 25 mg of silica, (dichloromethane: ethyl acetate 1:0 gradually changing to 0.1) to obtain 1.17 g (84%) of the 2-methyl-2-propen-1-ol as colorless crystals melting at 116°-8° C. μ_(Max) (KBr)3160, 2960, 2920, 2870 and 1610 cm⁻¹

A solution of 1.4 g (4.78 mmol) of 2-methyl-2-propen-1-ol in 200 ml of chloroform was heated under reflux with 5 g of manganese dioxide for 2 hours and then was filtered hot through celite. The solvent was removed under reduced pressure to obtain 1.25 g (90%) of 1-(6-ethyl-5-methyl-7-methylthioimidazo[1,2-a]pyrimidin-2-yl)-2-methyl-2-propen-1-one as yellow crystals melting at 136°-7° C. (from ethyl acetate).

STEP B: 1-(3-bromo-6-ethyl-5-methyl-7-methylthioimidazo[1,2-a]pyrimidin-2-yl)-2-methyl-2-propen-1-one Method B:

A solution of 1.0 g (3.63 mmol) of 1-(6-ethyl-5-methyl-7-methylthioimidazo[1,2-a]pyrimidin-2-yl)-2-methyl-2-propen-1-one in 50 ml of chloroform was treated with 0.71 g (4.0 mmol) of N-bromo succinimide. After 20 minutes at room temperature, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica, 25 g: dichloromethane) to obtain 1.1 g (87%) of 1-(3-bromo-6-ethyl-5-methyl-7-methylthioimidazo[1,2-a]pyrimidin-2-yl)-2-methyl-2-2-propen-1-one in the form of pale yellow crystals melting at 87°-9° C.

EXAMPLES 2 to 13

Using the procedure of Step A and/or Step B of Example 1, the compounds of Examples 2 to 13 were prepared.

Example 2: (3-bromo 6-ethyl 7-methoxy 5-methylimidazo [1,2-a] pyrimidin-2-yl) isopropenyl methanone.

Example 3: (3-chloro 6-ethyl 7-methoxy 5-methylimidazo [1,2-a] pyrimidin-2-yl) isopropenyl methanone.

Example 4: (7-methoxy 5-methylimidazo [1,2-a] pyrimidin-2-yl) ethenyl methanone.

Example 5: (3-bromo 6-ethyl 7-methoxy 5-methylimidazo [1,2-a] pyrimidin-2-yl) ethenyl methanone.

Example 6: [1-(4-ethylphenyl) 2-imidazol-4-yl] isopropenyl methanone.

Example 7: [1-(4-ethylphenyl) 5-bromo 2-thiomethylimidazol-4-yl] isopropenyl methanone.

Example 8: [1-(4-methoxyphenyl) 5-bromo 2-thiomethylimidazol-4-yl] isopropenyl methanone.

Example 9: [1-(4-methoxyphenyl) 5-chloro 2-thiomethylimidazol-4-yl] isopropenyl methanone.

Example 10: [1-(4-methylphenyl) 5-bromo 2-thiomethylimidazol-4-yl] isopropenyl methanone.

Example 11: [1-(4-methylphenyl) 5-bromo 2-thioisopropylimidazol-4-yl] isopropenyl methanone.

Example 12: [1-(4-fluorophenyl) 5-bromo 2-thiomethylimidazol-4-yl] isopropenyl methanone.

Example 13: [1-(4-methoxyphenyl) 5-bromo 2-thiomethylimidazol-4-yl] ethenyl methanone.

EXAMPLE 14 [5-bromo-1-(4-hydroxyphenyl)-2-methylthioimidazol-4-yl]-2-methyl-2-propen-1-one STEP A: 1-(4-benzyloxyphenyl)-2-methylthioimidazole-4-carboxaldehyde

p-benzyloxyaniline was reacted according to method of preparation A to obtain 1-(4-benzyloxyphenyl)-2-methylthioimidazole-4-carboxaldehyde

STEP B: [1-(4-benzyloxyphenyl)-2-methylthioimidazol-4-yl]2-methyl-2-propen-1-one

The compound of Step A was reacted by the method of Step A of Example 1 to obtain [1-(4-benzyloxyphenyl)-2-methylthioimidazol-4-yl]-2-methyl-2-propen-1-one

STEP C: [1-(4-benzyloxyphenyl)-5-bromo-2-methylthioimidazol-4-yl]-2-methyl-2-propen-1-one

The product of Step B was reacted by the method of Step B of Example 1 to obtain [1-(4-benzyloxyphenyl)-5-bromo-2-methylthioimidazol-4-yl]-2-methyl-2-propen-1-one.

STEP D: [5-bromo-1-(4-hydroxyphenyl)-2-methylthioimidazol-4-yl]-2-methyl-2-propen-1-one

2.7 g (6.1 mmol) of [1-(4-benzyloxyphenyl)-5-bromo-2-methylthioimidazol-4-yl]-2-methyl-2-propen-1-one were heated for 24 hours at 30° C. in 25 ml of trifluoroacetatic acid. Removal of trifluoroacetic acid was effected at 30° C. under reduced pressure followed by addition of iced water to obtain an oil which was extracted with ether and purified by flash chromatography on silica (5% ethyl acetate in petroleum ether) to obtain 1.9 g (88%) of [5-bromo-1-(4-hydroxyphenyl)-2-methylthioimidazol-4-yl]2methyl-2-propen-1-one in the form of pale yellow crystals melting at 159°-161° C.

EXAMPLE 15 (1-ethyl 5-bromo 2-thioisopropyl imidazol-4-yl) isopropenyl methanone

Using the method of Example 1, the corresponding compound of formula I_(A) was reacted to obtain the compound of Example 15

EXAMPLE 16 [5-chloro-1-(4-ethylphenyl)-2-(prop-2-ylsulfinyl)-imidazol-4-yl]-2-methyl-2-propen-1-one

A mixture of 3.0 g (8.6 mmol) of [5-chloro-1-(4-ethylphenyl)-2-(propen-2-ylthio)-imidazol-4-yl]-2-methyl-2-propen-1-one and 2.3 g (11 mmol) of sodium metaperiodate was heated at 50° C. for 3 hours in 30 ml of 90% aqueous methanol. The mixture was cooled and poured into water. Extraction with dichloromethane yielded an oil which was purified by flash chromatography on silica (20% ethyl acetate in petroleum ether) to obtain 1.3 g (41%) of [5-chloro-1-(4-ethylphenyl)-2-(prop-2-ylsulfinyl)-imidazol-4-yl]-2-methyl-2-propen-1-one as cream-colored crystals melting at 83°-4° C.

EXAMPLE 17 [1-(4-ethylphenyl) 5-chloro 2-ethylsulfinylimidazol-4-yl]isopropenyl methanone

Using the method of Example 16, the corresponding compound of formula I_(C) was reacted to obtain the compound of Example 17.

EXAMPLES 18 to 21

Using the methods of Step A or B of Example 1, the corresponding compounds of formulae II or I_(A) respectively were reacted to obtain the compounds of Examples 18 to 21.

Example 18: (6-ethyl 7-methoxy 5-methylimidazo [1,2-a] pyrimidin-2-yl)phenylethynyl methanone.

Example 19: 1-(6-ethyl 7-methoxy 5-methylimidazo [1,2-a] pyrimidin-2-yl)(3,3-dimethylbut-1-ynyl) methanone.

Example 20: (3-bromo 6-ethyl 7-methoxy 5-methylimidazo [1,2-a] pyrimidin-2-yl)(3,3-dimethylbut-1-ynyl) methanone.

Example 21: (3-bromo 6-ethyl 7-methoxy 5-methylimidazo [1,2-a] pyrimidin-2-yl) (2-phenylethy-1-yl) methanone.

EXAMPLE 22 1-(3-bromo-6-ethyl-7-methoxy-5-methyl-imidazo[1,2-a]pyrimidin-2-yl)-4-hydroxy-2-butyn-1-one STEP A: 1-(6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-(tetrahydropyran-2-yloxy)-2-butyn-1-one

6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-carboxaldehyde and 3-(tetrahydropyran-2-yloxy)-1-propynyl-magnesium bromide [J. Chem. Soc., 1950, 3646] were reacted by the method of Step A of Example 1 to obtain 1-(6-ethyl-7-methoxy-5-methylimidazol[1,2-a]pyrimidin-2-yl)-4-(tetrahydropyran-2-yloxy)-2-butyn-1-one.

STEP B: 1-(3-bromo-6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-(tetrahydropyran-2-yloxy)-2-butyn-1-one

The compound of Step A was reacted by the procedure of Step B of Example 1 to obtain 1-3-(bromo-6-ethyl-7-methoxy-5-methylmidazo[1,2-a]pyrimidin-2-yl)-4-(tetrahydropyran-2-yloxy)-2-butyn-1-one.

STEP C: 1-(3-bromo-6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-hydroxy-2-butyn-1-one

A solution of 5.0 g (11.5 mmol) of 1-(3-bromo-6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-(tetrahydropyran-2-yloxy)-2-butyn-1-one in a mixture of 100 ml of methanol and 35 ml of 2N hydrochloric acid stood at room temperature for 30 minutes and then was neutralized with aqueous sodium bicarbonate. Extraction with chloroform gave an oil which was chromatographed over silica (chloroform: ether: methanol 100:0:0 gradually changing to 0:95:5) to obtain 1.3 g (32%) of 1-(3-bromo-6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-hydroxy-2-butyn-1-one as off-white crystals melting at 212°-3° C. (decomp.).

EXAMPLE 23 1-(6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-hydroxy-2-butyn-1-one STEP A: 1-(6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-(tetrahydropyran-2-yloxy)-2-butyn-1-one

Using the procedure of Step A of Example 22, 1-(6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-(tetrahydropyran-2-yloxy)-2-butyn-1-one was prepared.

STEP B: 1-(6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-hydroxy-2-butyn-1-one

Using the method of Step C of Example 22, the compound of Step A was reacted to obtain a 1-(6-ethyl-7-methoxy-5-methylimidazol[1,2-a]pyrimidin-2-yl)-4-hydroxy-2-butyn-1-one

EXAMPLES 24 to 28

Using the methods of Step A or B of Example 1, the corresponding compounds of formulae II or I_(A) respectively were reacted to obtain the compounds of Examples 24 to 28. The yield, melting point and analytical data of compounds of formula I are given in Tables 1 to 4.

Example 24: (3-bromo 6-ethyl 7-methoxy 5-methylimidazo [1,2-a] pyrimidin-2-yl) (propyn-1-ynyl) methanone.

Example 25: (3-bromoimidazo [1,2-a] pyridin-2-yl) isopropenyl methanone (chlorhydrate).

Example 26: (imidazo [1,2-a] pyridin-2-yl) isopropenyl methanone.

Example 27: (imidazo [1,2-a] pyridin-2-yl) (2-phenylethyn-1-yl) methanone.

Example 28 : 3-bromoimidazo [1,2-a] pyridin-2-yl (2-phenylethyn-1-yl) methanone.

                                      TABLE A                                      __________________________________________________________________________      ##STR23##                                                                                      Yield                                                                              IR (KBr disc)                                                                          M.p.           Theory/Found (%)                   PREP                                                                               G  D         (%) (cm.sup.-1)                                                                            (°C.)                                                                       Formula                                                                               M.W.                                                                               C  H   N                           __________________________________________________________________________     A   MeS                                                                                ##STR24##                                                                               49  3130, 1690, 1670                                                                       118-20                                                                             C.sub.12 H.sub.12 N.sub.2 O.sub.2                                                     248.3                                                                              58.05 57.65                                                                       4.87 4.88                                                                          11.28 11.09                 B   MeS                                                                                ##STR25##                                                                               80  3130, 1668, 1650                                                                       88-90                                                                              C.sub.13 H.sub.14 N.sub.2 OS                                                          246.3                                                                              63.39 63.44                                                                       5.73 5.73                                                                          11.37 11.41                 C   MeS                                                                                ##STR26##                                                                               83  1680    111-3                                                                              C.sub.12 H.sub.12 N.sub.2 OS                                                          232.3                                  D   iPrS                                                                               ##STR27##                                                                               75  1670    63-4                                                                               C.sub.14 H.sub.16 N.sub.2 OS                                                          260.3                                  E   MeS                                                                                ##STR28##                                                                               90  1690, 1675                                                                             130-1                                                                              C.sub.11 H.sub.9 FN.sub.2 OS                                                          236.3                                  __________________________________________________________________________

                                      TABLE B                                      __________________________________________________________________________      ##STR29##                                                                                 Yield                                                                              IR (KBr disc)                                                                           M.P.           Theory/Found (%)                       PREP                                                                               X  Y Y' (%) (cm.sup.-1)                                                                             (°C.)                                                                       Formula                                                                               M.W.                                                                               C  H  N  S                             __________________________________________________________________________     F   MeO                                                                               Et                                                                               Me 72  3120, 3000, 2980,                                                                       185-6                                                                              C.sub.11 H.sub.13 N.sub.3 O.sub.2                                                     219.2                                                                              60.26                                                                             5.98                                                                              19.17                                            2950, 1690, 1640        59.97                                                                             5.97                                                                              19.05                            G   MeS                                                                               Et                                                                               Me 85  3098, 2960, 2915,                                                                       203-4                                                                              C.sub.11 H.sub.13 N.sub.3 OS                                                          235.3                                                                              56.15                                                                             5.58                                                                              17.85                                                                             13.63                                         2860, 1675, 1610        56.35                                                                             5.58                                                                              17.95                                                                             13.34                         __________________________________________________________________________

                                      TABLE C                                      __________________________________________________________________________      ##STR30##                                                                                        IR (KBr disc)                                                                           M.p.           Theory/Found (%)                    PREP                                                                               X  Y Y' R  (%) (cm.sup.-1)                                                                             (°C.)                                                                       Formula                                                                               M.W.                                                                               C  H  N  S                          __________________________________________________________________________     H   MeS                                                                               Et                                                                               Me Me 76  2970, 1630, 1615                                                                        136-7                                                                              C.sub.14 H.sub.17 N.sub.3 OS                                                          275.4                                                                              61.06                                                                             6.24                                                                              15.25                                                                             11.64                                                                 60.91                                                                             6.22                                                                              15.17                                                                             11.54                      J   MeO                                                                               Et                                                                               Me Me 35  3130, 1640                                                                              148-50                                                                             C.sub.14 H.sub.17 N.sub.3 O.sub.2                                                     259.3                                                                              64.85                                                                             6.61                                                                              16.20                                                                    64.67                                                                             6.57                                                                              16.12                         K   MeO                                                                               H Me Me 56  3150, 2980, 2950,                                                                       151 C.sub.12 H.sub.13 N.sub.3 O.sub.2                                                     231.25                                                                             62.32                                                                             5.68                                                                              18.16                                            1625                    62.20                                                                             5.70                                                                              18.14                         __________________________________________________________________________

                                      TABLE 1                                      __________________________________________________________________________      ##STR31##                                                                                            IR (KBr                                                                Meth-                                                                              Yield                                                                              disc) M.p.         Theory/Found (%)                     Ex.                                                                              X  Y Y' E R  od  (%) (cm.sup.-1)                                                                               Formula M.W.                                                                               C  H  N  Hal  S.sup.1            __________________________________________________________________________     1 MeS                                                                               Et                                                                               Me Br                                                                               Me B   87  2960, 2920,                                                                          87-9 C.sub.14 H.sub.16 BrN.sub.3 OS                                                         354.3                                                                              47.46                                                                              4.56                                                                             11.86                                                                             22.55(Br)                                                                           9.05                                      1640, 1600             47.32                                                                             4.56                                                                              11.82                                                                             22.54                                                                               9.02               2 MeO                                                                               Et                                                                               Me Br                                                                               Me B   87  2960, 1635,                                                                          101-2                                                                               C.sub.14 H.sub.16 BrN.sub.3 O.sub.2                                                    338.2                                                                              49.71                                                                             4.78                                                                              12.42                                                                             23.63(Br)                                      1625                   49.73                                                                             4.72                                                                              12.31                                                                             23.67                   3 MeO                                                                               Et                                                                               Me Cl                                                                               Me B   62  2965, 1625                                                                           111-2                                                                               C.sub.14 H.sub.16 ClN.sub.3 O.sub.2                                                    293.8                                                                              57.24                                                                             5.50                                                                              14.30                                                                             12.07(Cl)                                                             57.03                                                                             5.49                                                                              14.25                                                                             12.17                   4 MeO                                                                               H Me Br                                                                               Me B   98  3070, 2950,                                                                          145-6                                                                               C.sub.12 H.sub.12 BrN.sub.3 O.sub.2                                                    310.15                                                      1630  decomp                                            5 MeO                                                                               Et                                                                               Me Br                                                                               H  B   47  2970, 2940,                                                                          120-3                                                                               C.sub.13 H.sub.14 BrN.sub.3 O.sub.2                                                    324.2                                                                              48.16                                                                             4.36                                                                              12.96                                                                             24.65(Br)                                      2875, 1670,                                                                          decomp           48.05                                                                             4.32                                                                              12.73                                                                             24.45                                          1625                                                    __________________________________________________________________________

                                      TABLE 2                                      __________________________________________________________________________      ##STR32##                                                                     __________________________________________________________________________     Ex-                        IR (KBr                                             am-                Meth-                                                                              Yield                                                                              disc) M.p.             Theory/Found (%)             ple                                                                               G   D      E R  od  (%) (cm.sup.-1)                                                                          (°C.)                                                                       Formula  M.W.                                                                               C  H  N  S                   __________________________________________________________________________     6  MeS                                                                                 ##STR33##                                                                            H Me A   43  3120, 1636,1626, 1611                                                                46-7                                                                               C.sub.16 H.sub.18 N.sub.2 OS                                                            286.4                                                                              67.1067.18                                                                        6.336.24                                                                          9.789.77                                                                          11.1911.23          7  MeS                                                                                 ##STR34##                                                                            Br                                                                               Me B   77  1636, 1620                                                                           94-6                                                                               C.sub.16 H.sub.17 BrN.sub.2 OS                                                          365.3                                                                              52.6152.62                                                                        4.694.69                                                                          7.677.67               __________________________________________________________________________     Ex-                                                                            am-                Meth-                                                                              Yield                                                                              IR    M.p.             Theory/Found (%)             ple                                                                               G   D      E R  od  (%) (cm.sup.-1)                                                                          (°C.)                                                                       Formula  M.W.                                                                               C  H  N  Other               __________________________________________________________________________     8  MeS                                                                                 ##STR35##                                                                            Br                                                                               CH.sub.3                                                                          B   84  1630, 1620,1605                                                                      128-9                                                                              C.sub.15 H.sub.15 BrN.sub.2 O.sub.2                                            S        367.3                                                                              49.0548.86                                                                        4.124.10                                                                          7.637.55                                                                          21.76(Br)21.74                                                                 3                   9  MeS                                                                                 ##STR36##                                                                            Cl                                                                               CH.sub.3                                                                          B   93  1630, 1620,1600                                                                      110-1                                                                              C.sub.15 H.sub.15 ClN.sub.2 O.sub.2                                            S        322.8                                                                              55.8155.12                                                                        4.684.74                                                                          8.688.53                                                                          10.98(Cl)11.39                                                                 1                   10 MeS                                                                                 ##STR37##                                                                            Br                                                                               CH.sub.3                                                                          B   52  1630, 1610                                                                           89-90                                                                              C.sub.15 H.sub.15 BrN.sub.2 OS                                                          351.3                                                                              51.2951.09                                                                        4.304.29                                                                          7.987.89                                                                          22.75(Br)22.83                                                                 .                   11 iPRS                                                                                ##STR38##                                                                            Br                                                                               CH.sub.3                                                                          B   66  1635, 1615,1605                                                                      135-6                                                                              C.sub.17 H.sub.19 BrN.sub.2 OS                                                          379.3                                                                              53.8353.76                                                                        5.055.07                                                                          7.397.33                                                                          8.45(S)8.43         12 MeS                                                                                 ##STR39##                                                                            Br                                                                               CH.sub.3                                                                          B   75  1635, 1595                                                                           99-101                                                                             C.sub.14 H.sub.12 BrFN.sub.2                                                            355.2                                                                              47.3347.37                                                                        3.413.48                                                                          7.817.81                                                                          9.02(S)9.05         13 MeS                                                                                 ##STR40##                                                                            Br                                                                               H  B   68  1655, 1600                                                                           117-9                                                                              C.sub.14 H.sub.13 BrN.sub.2 O.sub.2                                            S        353.2                                                                              47.6047.36                                                                        3.713.75                                                                          7.937.79                                                                          22.62(Br)22.72                                                                 7                   14 MeS                                                                                 ##STR41##                                                                            Br                                                                               CH.sub.3                                                                          B   86  3220, 1610,1590                                                                      159-61                                                                             C.sub.14 H.sub.13 BrN.sub.2 O.sub.2                                            S        353.2                                                                              47.6047.63                                                                        3.713.72                                                                          7.937.82               15 iPRS                                                                               Et     Br                                                                               CH.sub.3                                                                          B   53  2960, 1635,                                                                          oil C.sub. 12 H.sub.17 BrNO.sub.2                                                           317.2                                                                              45.43                                                                             5.40                                                                              8.83                                              1590                   44.98                                                                             5.37                                                                              8.69                   16 iPrSO                                                                               ##STR42##                                                                            Cl                                                                               CH.sub.3                                                                          C   41  1640, 1610,1595                                                                      83-4                                                                               C.sub.18 H.sub.21 ClN.sub.2 O.sub.2                                            S        364.8                            17 EtSO                                                                                ##STR43##                                                                            Cl                                                                               CH.sub.3                                                                          C   33  1640, 1610,1600                                                                      76-8                                                                               C.sub.17 H.sub.19 ClN.sub.2 O.sub.2                                            S        350.8                            __________________________________________________________________________

                                      TABLE 3                                      __________________________________________________________________________      ##STR44##                                                                                             Yield     M.p.             Theory/Found (%)            Ex X  Y Y' E R'    Method                                                                              (%) IR (cm.sup.-1)                                                                       (°C.)                                                                        Formula M.W.                                                                               C  H  N  Hal                __________________________________________________________________________     18 MeO                                                                               Et                                                                               Me H Ph    A    86  2197, 1630                                                                           194-6                                                                               C.sub.19 H.sub.17 N.sub.3 O.sub.2                                                      319.4                                                                              71.46                                                                             5.37                                                                              13.16                                                                    71.33                                                                             5.42                                                                              13.11                 19 MeO                                                                               Et                                                                               Me H  .sub.-t-Bu                                                                          A    71  2965, 2215,                                                                          133-5                                                                               C.sub.17 H.sub.21 N.sub.3 O.sub.2                                                      299.3                                                                              68.21                                                                             7.07                                                                              14.04                                             1635                   68.19                                                                             7.09                                                                              14.06                 20 MeO                                                                               Et                                                                               Me Br                                                                                .sub.-t-Bu                                                                          B    86  2970, 2930,                                                                          186-7                                                                               C.sub.17 H.sub.20 BrN.sub.3                                                    O.sub.2 378.3                                                                              53.97                                                                             5.34                                                                              11.10                                                                             21.12                                          2870, 2200,            53.72                                                                             5.33                                                                              10.97                                                                             (Br)                                           1640, 1620                      20.89              21 MeO                                                                               Et                                                                               Me Br                                                                               Ph    B    79  3050, 2960,                                                                          187-190                                                                             C.sub.19 H.sub.16 BrN.sub.3                                                    O.sub.2 398.3                                                                              57.30                                                                             4.06                                                                              10.55                                                                             20.06                                          2920, 2200,            57.24                                                                             4.09                                                                              10.45                                                                             (Br)                                           1630                            20.11              22 MeO                                                                               Et                                                                               Me H CH.sub.2 OH                                                                          A    41  3400, 3125,                                                                          176-186                                                                             C.sub.14 H.sub.15 N.sub.3 O.sub.3                                                      273.3                                                                              61.53                                                                             5.53                                                                              15.38                                             2210, 1635                                                                           (decomp)                                     23 MeO                                                                               Et                                                                               Me Br                                                                               CH.sub.2 OH                                                                          B    28  3250, 2980,                                                                          212-3                                                                               C.sub.14 H.sub.14 BrN.sub.3 O.sub.                                             3       352.2                                                                              47.74                                                                             4.01                                                                              11.93                                                                             22.69                                          2880, 2220,                                                                          (decomp)         47.63                                                                             4.08                                                                              11.78                                                                             (Br)                                           1630                            22.36              24 MeO                                                                               Et                                                                               Me Br                                                                               CH.sub.3                                                                             B    93  2960, 2230,                                                                          170-2                                                                               C.sub.14 H.sub.14 BrN.sub.3                                                            320.2                                                                              52.51                                                                             4.42                                                                              13.12                                                                             24.96                                          2205, 1630                                                                           (decomp)                  (Br)               __________________________________________________________________________

                                      TABLE 4                                      __________________________________________________________________________      ##STR45##                                                                                            Yield        M.p.           Theory/Found (%)            Ex                                                                               X Y Y'                                                                               E R.sub.1 Method                                                                              (%) IR (cm.sup.-1)                                                                          (°C.)                                                                       Formula                                                                               M.W.                                                                               C  H  N  Hal                __________________________________________________________________________     25                                                                               H H H Br                                                                               CMeCH.sub.2                                                                            B    79  3070, 2540, 1650                                                                        140-2                                                                              C.sub.11 H.sub.9 BrN.sub.2                                                            301.6                                                                              43.81                                                                             3.35                                                                              9.28                                                      (HCl           43.57                                                                             3.41                                                                              9.11                                                      salt)                                      26                                                                               H H H H CMeCH.sub.2                                                                            A    77  3145, 3100, 3080,                                                                       93-4                                                                               C.sub.11 H.sub.10 N.sub.2                                                             186.2                                                                              70.95                                                                             5.42                                                                              15.04                                            3040, 1635              71.08                                                                             5.40                                                                              15.03                 27                                                                               H H H H CCPh    A    80  3140, 3100, 3080,                                                                       168 C.sub.16 H.sub.10 N.sub.2                                                             246.3                                                                              78.03                                                                             4.10                                                                              11.37                                            3050, 2190, 1630        77.96                                                                             4.23                                                                              11.31                 28                                                                               H H H Br                                                                               CCPh    B    74  3080, 3050, 2200                                                                        133-4                                                                              C.sub.16 H.sub.9 BrN.sub.2                                                            325.15                                                                             59.10                                                                             2.80                                                                              8.61                                                                              24.57                                         1630                    59.01                                                                             2.92                                                                              8.60                                                                              (Br)                                                                           24.66              __________________________________________________________________________

EXAMPLE 29

Tablets containing 20 mg of the compound of Example 1 or 7 and sufficient excipient of lactose, starch, talc and magnesium stearate for a final tablet weight of 100 mg were prepared.

BIOCHEMICAL ACTIVITY

The inhibition of ionophore-stimulated release of free arachidonic acid from [¹⁴ C]-arachidonic acid pre-labelled rat peritoneal neutrophils was studied using modifications of the method of Ahnfelt-Ronne and Arrigoni-Martelli [Biochemical Pharmacol., (1982) Vol. 31, p. 2619]. The results below show the micromolar concentrations of test compound required to inhibit, by 50% compared to controls, the release of radiolabelled products into supernatant liquid (IC₅₀ - μM).

    ______________________________________                                         Example              IC.sub.50 -μM                                          ______________________________________                                         1                    6.8                                                       2                    17                                                        3                    21                                                        4                    7.4                                                       5                    1.7                                                       6                    3.8                                                       7                    2.5                                                       8                    7.2                                                       9                    9.1                                                       10                   10                                                        11                   3.7                                                       12                   15                                                        13                   2.3                                                       14                   >10                                                       15                   17                                                        16                   4.4                                                       17                   --                                                        18                   12                                                        19                   16                                                        20                   4.2                                                       21                   1.5                                                       22                   59                                                        23                   46                                                        24                   7.2                                                       25                   28                                                        26                   >100                                                      27                   41                                                        28                   5.2                                                       ______________________________________                                    

Various modifications of the compounds and methods of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is intended to be limited only as defined in the appended claims. 

What we claim is:
 1. A compound selected from the group consisting of compounds of the formula ##STR46## wherein R₁ is selected from the group consisting of ##STR47## and --C.tbd.C--R', R is selected from the group consisting of hydrogen and alkyl of 1 to 5 carbon atoms, R' is selected from the group consisting of hydrogen, alkyl and hydroxyalkyl of 1 to 5 carbon atoms, and aryl of 6 to 10 carbon atoms unsubstituted or substituted with at least one member of the group consisting of halogen, --OH, --COOH, --CF₃ and alkyl and alkoxy of 1 to 5 carbon atoms, A is alkyl of 1 to 5 carbon atoms, B and G together with the carbon atom to which they are attached are carbonyl or thiocarbonyl and D is selected from the group consisting of alkyl of 1 to 5 carbon atoms and phenyl unsubstituted or substituted with at least one member of the group consisting of halogen, --OH, --COOH, --CF₃ and alkyl and alkoxy of 1 to 5 carbon atoms and E is hydrogen or halogen and its non-toxic, pharmaceutically acceptable acid addition salts.
 2. A compound of claim 1 wherein E is halogen.
 3. An anti-inflammatory composition comprising an anti-inflammatorily effective amount of at least one compound of claim 1 and an inert pharmaceutical carrier.
 4. A composition of claim 3 wherein E is halogen.
 5. A method of relieving inflammation in warm-blooded animals comprising administering to warm-blooded animals an anti-inflammatorily effective amount of at least one compound of claim
 1. 6. A method of claim 5 wherein E is halogen. 